title: The effect of peroxisome proliferator-activated receptor-γ ligands on in vitro and in vivo models of COPD.
abstract: Peroxisome proliferator-activated receptor (PPAR)-γ is expressed in alveolar macrophages. The anti-inflammatory potential of the PPAR-γ ligands rosiglitazone and pioglitazone were investigated using in vitro alveolar macrophage models and in vivo animal models relevant to chronic obstructive pulmonary disease (COPD). PPAR-γ protein and gene expression in COPD alveolar macrophages was compared with control smokers and never-smokers. COPD macrophages were used to investigate the effects of PPAR-γ ligands and corticosteroids on lipopolysaccharide-induced cytokine production, alternative macrophage activation (M2) gene expression and efferocytosis. The effects of PPAR-γ ligands in a subchronic tobacco smoke model in mice were investigated. PPAR-γ protein expression was similar in COPD patients compared to controls, although increased gene expression levels were observed in COPD patients and control smokers compared to never-smokers. PPAR-γ ligands reduced tumour necrosis factor-α and CC chemokine ligand-5, but not CXC chemokine ligand-8, in COPD alveolar macrophages; these effects were generally less than those of the corticosteroid dexamethasone. Rosiglitazone increased M2 gene expression and enhanced efferocytosis of apoptotic neutrophils. Rosiglitazone and pioglitazone attenuated airway neutrophilia in a corticosteroid-resistant mouse model of pulmonary inflammation. We show biological actions of PPAR-γ agonists on corticosteroid-resistant disease, tobacco smoke-induced pulmonary inflammation, skewing of macrophage phenotype and clearance of apoptotic neutrophils.
authors.affiliation: NIHR Translational Research Facility, University Hospital of South Manchester, Manchester.
authors.forename: Simon
authors.initials: S
authors.lastname: Lea
authors.forename: Jonathan
authors.initials: J
authors.lastname: Plumb
authors.forename: Hannah
authors.initials: H
authors.lastname: Metcalfe
authors.forename: Dianne
authors.initials: D
authors.lastname: Spicer
authors.forename: Paul
authors.initials: P
authors.lastname: Woodman
authors.forename: J Craig
authors.initials: JC
authors.lastname: Fox
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
mesh_terms: D000305:Adrenal Cortex Hormones / Q000737:chemistry; D000368:Aged; D000818:Animals; D017209:Apoptosis; D018946:Chemokine CCL5 / Q000378:metabolism; D003907:Dexamethasone / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology*; D000077154:Rosiglitazone; D012907:Smoking / Q000009:adverse effects; D045162:Thiazolidinediones / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; C483024:CCL5 protein, human; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D007004:Hypoglycemic Agents; D016209:Interleukin-8; D008024:Ligands; D008070:Lipopolysaccharides; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D003907:Dexamethasone; D000077205:Pioglitazone